1. Field of the Invention
The invention relates generally to a therapeutic composition and introduction of the composition to certain target cell populations in a vascular region, such as smooth muscle cells, requiring modulation to ameliorate a diseased state, particularly for the treatment of stenosis or restenosis following a vascular trauma or disease. More particularly, the invention relates to methods of local and systemic administration of actinomycin D for the treatment of a vascular disease such as restenosis.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is widely used as the primary treatment modality in many patients with coronary artery disease. PTCA can relieve myocardial ischemia in patients with coronary artery disease by reducing lumen obstruction and improving coronary flow. Recurrent stenosis or restenosis, characterized by the reocclusion of the coronary arteries following PTCA, remains a significant problem, however. Occurrence of immediate occlusion or development of restenosis within 6 months after the procedure results in significant morbidity and mortality or frequently necessitates further interventions such as repeat angioplasty or coronary bypass surgery.
The processes responsible for restenosis after PTCA are not completely understood but may be caused by complex interplay among several different biological agents and pathways. It has been theorized that the etiology of the disease process includes: (1) a shift in smooth muscle phenotype from a quiescent, contractile state to a migrating, proliferative from; (2) migration of the transformed smooth muscle cell from the media to the intima; and (3) massive proliferation of smooth muscle cells in the intima. Investigations of the pathogenesis of intima thickening have produced a theory that, following arterial injury, platelets, endothelial cells, macrophages and smooth muscle cells release various cytokines such as interleukin-1 (1L-1) and paracrine and autocrine growth factors such as platelet derived growth factor, epidermal growth factor, insulin-like growth factor, and fibroblast growth factor. T-cells and macrophages also migrate into the neointima. This cascade of events, as it has been suggested, results in an excessive proliferation and migration of smooth muscle cells, which causes the narrowing of the blood vessel and the reduction of the flow of blood through the vessel.
No surgical intervention or post-surgical treatment, to date, has proven significantly effective in preventing restenosis. Treatment strategies have included repeat angioplasty remodeling or the implantation of stents. Stents are scaffoldings, usually cylindrical or tubular in shape, which function to physically hold open and, if desired, to expand the wall of the passageway. Typically stents are capable of being compressed, so that they can be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Mechanical intervention via stents, although a significant innovation in the treatment of occlusive regions, has not reduced the development of restenosis.
Pharmaceutical agents have also been locally and systemically administered, concurrent with or following PTCA, in an attempt to inhibit smooth muscle cell hyper-proliferation. The pharmaceutical agents employed in an attempt to treat restenosis have shown some favorable result. However, there is a great need for better and more effective compounds, and methods of using the compounds, to inhibit smooth muscle cell hyper-proliferation for the effective treatment of restenosis.
A composition and method of using the composition to inhibit the activity of vascular smooth muscle cells is provided. The composition inhibits abnormal or inappropriate migration and proliferation of smooth muscle cells. In one embodiment, the composition is actinomycin D or analogs or derivatives thereof. In another embodiment, the composition can be a combination of actinomycin D, or analogs or derivatives thereof, and at least one bioactive agent.
In accordance with one embodiment, a method is provided for inhibiting restenosis of a blood vessel by administering to a mammal the composition of the invention. Restenosis can be caused by hyper-proliferation of smooth muscle cells which can be initiated as a result of vascular trauma associated with treatment procedures such as angioplasty, stent placement, or grafting. The composition can be administered locally, systemically, orally or parenterally. The administration can be before, during or after the occurrence of the vascular trauma. Local administration can be, for example, via catheters or implantable prostheses such as stents, grafts, and polymeric carriers. In one suitable embodiment, self-expandable stents can be used for delivering the composition.
In accordance with another embodiment, a medical device is provided comprising a prosthesis for implanting in a body passageway and actinomycin D, or analogs or derivatives thereof, carried by the prosthesis. The actinomycin D, or analogs or derivatives thereof, can be released from the prosthesis in the body passageway. Examples of the prosthesis can include balloon-expandable stents, self-expandable stents, grafts, polymeric carriers, and particles. A therapeutic agent can also be carried by the prosthesis and used in combination with the actinomycin D, or analogs and derivatives thereof. The prosthesis can have a micro-porous structure and/or the prosthesis can be coated with a polymeric layer such as an ethylene vinyl alcohol copolymer layer.
In accordance with another embodiment, a therapeutic method is provided for treating a mammalian blood vessel. The method comprises administering to a mammal actinomycin D, or analogs or derivatives thereof, and implanting a self-expandable stent at a selected region of the mammalian blood vessel. Actinomycin D, or analogs or derivatives thereof, induces positive remodeling of the internal elastic lamina of the blood vessel wall and in response the self-expandable stent increases is diameter as the internal elastic lamia is positively remodeled. The actinomycin D, or analogs or derivatives thereof, can be administered prior to, contemporaneously with, or subsequent to the implantation of the self-expandable stent. In one embodiment, the self-expandable stent is coated with a polymeric material and the actinomycin D, or analogs or derivatives thereof, is impregnated in the polymeric coating for sustained release. The self-expandable stent can also contain cavities for releasably containing the actinomycin D, or analogs or derivatives thereof.
In accordance with another embodiment, a method for positively remodeling a layer of a blood vessel wall is provided. Actinomycin D is administered to a blood vessel to positively remodel the layer of the blood vessel wall.